Captopril

d. Therapy may be initiated as early as three days following a myocardial infarction. d. d. d. over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY). , thrombolytics, aspirin, beta blockers. d. Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril tablets if additional therapy is required to further lower blood pressure.

Dosage Adjustment in Renal Impairment Because captopril tablets are excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function.

Therefore, these patients may respond to smaller or less frequent doses. Accordingly, for patients with significant renal impairment, initial daily dosage of captopril tablets should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals).

After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. , furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment.

(see WARNINGS: Anaphylactoid Reactions During Membrane Exposure and PRECAUTIONS: Hemodialysis).

Dysgeusia Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration.

Weight loss may be associated with the loss of taste. Angioedema Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction (see WARNINGS: Head and Neck Angioedema, Intestinal Angioedema and PRECAUTIONS: Information for Patients).

5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General: Cough). 5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.

Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

Body as a Whole:

Anaphylactoid reactions (see WARNINGS: Anaphylactoid and Possible Related Reactions and PRECAUTIONS: Hemodialysis).

General:

Asthenia, gynecomastia.

Cardiovascular:

Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.

Dermatologic:

Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.

Gastrointestinal:

Pancreatitis, glossitis, dyspepsia.

Hematologic:

Anemia, including aplastic and hemolytic.

Hepatobiliary:

Jaundice, hepatitis, including rare cases of necrosis, cholestasis.

Metabolic:

Symptomatic hyponatremia.

Musculoskeletal:

Myalgia, myasthenia.

Nervous/Psychiatric:

Ataxia, confusion, depression, nervousness, somnolence.

Respiratory:

Bronchospasm, eosinophilic pneumonitis, rhinitis.

Special Senses:

Blurred vision.

Urogenital:

Impotence. As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Altered Laboratory Findings Serum Electrolytes Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS).

Hyponatremia: particularly in patients receiving a low sodium diet or concomitant diuretics. BUN/Serum Creatinine Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur.

Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. Hematologic A positive ANA has been reported. Liver Function Tests Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Neutropenia/Agranulocytosis Neutropenia (< 1000/mm3) with myeloid hypoplasia has resulted from use of captopril.

About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. 6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed.

6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function.

S. reports. 7 percent of patients in clinical trials. While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. 6 mg/dL and more than 75 percent were in patients also receiving procainamide.

In heart failure, it appears that the same risk factors for neutropenia are present. The neutropenia has usually been detected within three months after captopril was started. , hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen.

In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors.

Evaluation of the hypertensive or heart failure patient should always include assessment of renal function. If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically.

In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution.

, sore throat, fever). If infection is suspected, white cell counts should be performed without delay. Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm3) the physician should withdraw captopril and closely follow the patient’s course.

7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about one- fifth of proteinuric patients.

In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria. Hypotension Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis (see PRECAUTIONS: Drug Interactions).

In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances it has been associated with arrhythmia or conduction defects.

6 percent of patients with heart failure. BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION. d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diuretic is increased.

In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure. Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood pressure is a common and desirable observation upon initiation of captopril tablets treatment in heart failure.

The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months. Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue captopril tablets as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mothers and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin- angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue captopril tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to captopril tablets for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS: Pediatric Use).

8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose.

Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.